As its overall goal this project seeks to understand the pathogenesis of nontoxic goiter, a common clinical problem which may lead to thyroid nodules and thyroid cancer. We are focussing on thyroglobulin, the major protein of the thyroid which serves both as matrix for hormone synthesis and a storage depot once hormones are formed. We are particularly interested in whether variations in thyroglobulin structure and in the handling of thyroglobulin can lead to abnormalities in hormone synthesis and goiter, and if so, what mechanisms are involved. Our main experimental approaches are as follows (1) We are examining the features of thyroglobulin structure which are important to thyroxine biosynthesis. We have isolated small discrete iodopeptides from thyroglobulin which are rich in thyroxine, and are studying their structure and their relation to the remainder of the molecule. (2) We are examining the products of thyroglobulin breakdown by thyroidal enzymes, and are characterizing the various endopeptidases and exopeptidases involved. (3) We have found that TSH alters several features of the structure of thyroglobulin, and are investigating this further. (4) Thyroglobulins from normal and goitrous glands are being isolated and studied individually. We have found there are significant variations among the amino acid composition of "normal" thyroglobulins, indicating structural heterogeneity for this protein. Thyroglobulins from goitrous glands and from thyroid carcinoma have shown more extensive deviations from the mean of the "normals." The relationship of these changes to thyroid disease is being examined further.